Atopic dermatitis (AD) is a biphasic inflammatory skin disease characterized by an initial phase predominated[unreadable] by Th2 cytokines which then shifts to a second, more chronic Th1 eczematous phase. Studies have shown[unreadable] that dendritic cells (DC) are important for the pathogenesis of AD. DC are considered the most potent antigen[unreadable] presenting cells (ARC) by virtue of their ability to bridge an innate immune response to an adaptive immune[unreadable] response. The status of DC at the time of priming CD4 T cells can determine the type of immunity, either T[unreadable] helper 1 (Th1) or Th2. Recently, we have demonstrated that, depending on the ability to produce IL-10, DC[unreadable] can direct either Th1 or Th2 immune responses. IL-10, a pleiotropic cytokine produced by many different cell[unreadable] types, inhibits antigen-specific activation and proliferation of T cells and ultimately leads to the termination of[unreadable] inflammatory responses. Thus, regulation of IL-10 can dramatically alter immune responses. IL-4, a Th2[unreadable] inducing cytokine, inhibits DC IL-10 expression and subsequently induces IL-12. Thus, DC exposed to IL-4[unreadable] secrete more IL-12 and promote Th1 instead of Th2 differentiation. These data demonstrate a complex[unreadable] cytokine regulatory network and indicate that the same cytokine has a distinct function modulating the immune[unreadable] response via ARC. We hypothesize that the ability of DC to produce IL-10 contributes to the pathogenesis[unreadable] of AD by directing the Th immune response. In early AD, DC are activated by allergen via toll-like receptors[unreadable] (TLR) and produce both inflammatory and anti-inflammatory cytokines directing Th2 development by secreting[unreadable] high IL-10 and as a result, low IL-12. As the disease progresses, the amount of IL-4 in the local environment[unreadable] is elevated and as a consequence DC will produce less IL-10 leading to a Th1 response. We will test this[unreadable] hypothesis in the current application by focusing on DC function and regulation of DC-mediated pathogenesis[unreadable] of AD using both animal models and human patients. Our long-term goal is to have a better understanding of[unreadable] AD pathogenesis mediated by DC, which will help us to design improved therapeutic tools in the future. To[unreadable] achieve this goal, we propose three specific aims. In Aim 1, we will investigate the role of TLR-mediated[unreadable] activation of DC with the hypothesis that TLR on DC are critical to activate DC when an allergen is[unreadable] encountered and for subsequent inflammation. Aim 2 will study DC-mediated immunity using transgenic mice[unreadable] that express a constitutively active form of State (StatGVT) as an AD model system. We hypothesize that[unreadable] DC functions are altered in these mice because StatGVT mice have elevated levels of Th2 cytokines including[unreadable] IL-4. The last Aim is devoted to studying DC function from AD patients by testing the wash fluid from the skin[unreadable] lesion and blood samples collected from patients. Using both an animal model that develops spontaneous[unreadable] AD-like symptoms as well as AD patients, we will obtain valuable information that will provide us a better[unreadable] understanding of DC-mediated immunity in AD and other allergic diseases.